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J Nucl Med. 2019 Feb 7. pii: jnumed.118.222034. doi: 10.2967/jnumed.118.222034. [Epub ahead of print]

Evaluation of 11C-LSN3172176 as a novel PET tracer for imaging M1 muscarinic acetylcholine receptors in non-human primates.

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Yale University, United States.
Eli Lilly, United States.


The M1 muscarinic acetylcholine receptor (mAChR) plays an important role in learning and memory, and therefore is a target for development of drugs for treatment of cognitive impairments in Alzheimer's disease and schizophrenia. The availability of M1-selective radiotracers for positron emission tomography (PET) will help in developing therapeutic agents by providing an imaging tool for assessment of drug dose-receptor occupancy relationship. Here we report the synthesis and evaluation of 11C-LSN3172176 (ethyl 4-(6-(methyl-11C)-2-oxoindolin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate) in non-human primates. Methods: 11C-LSN3172176 was radiolabeled via the Suzuki-Miyaura cross-coupling method. PET scans in rhesus macaques were acquired on the Focus-220 for 2 h with arterial blood sampling and metabolite analysis to measure the input function. Blocking scans with scopolamine (50 µg/kg) and the M1-selective agent AZD6088 (0.67 and 2 mg/kg) were performed to assess tracer binding specificity and selectivity. Regional brain time-activity curves (TACs) were analyzed with the one-tissue (1T) compartment model and the multilinear analysis method (MA1) to calculate regional distribution volume (VT). Non-displaceable binding potential (BPND) values were calculated using the cerebellum as reference region. Results: 11C-LSN3172176 was synthesized with >99% radiochemical purity and high molar activity. In rhesus monkeys 11C-LSN3172176 metabolized rapidly (29 ± 6% parent remaining at 15 min), and displayed fast kinetics and extremely high uptake in the brain. Imaging data were modeled well with the 1T and MA1 methods. MA1-derived VT values were high (range of 10-81 mL/cm3) in all known M1 mAChR-rich brain regions. Pre-treatment with scopolamine and AZD6088 significantly reduced the brain uptake of 11C-LSN3172176, thus demonstrating its binding specificity and selectivity in vivo. The cerebellum appeared to be a suitable reference region for derivation of BPND, which ranged from 2.42 in the globus pallidus to 8.48 in the nucleus accumbens. Conclusion: 11C-LSN3172176 exhibits excellent in vivo binding and imaging characteristics in non-human primates and appears to be the first appropriate radiotracer for PET imaging of human M1 AChR.


<sup>11</sup>C-LSN3172176; Animal Imaging; M<inf>1</inf>; Muscarinic; Nonhuman primate; PET; Radiopharmaceuticals; Scopolamine


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